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Export of Misfolded Proteins out of the ER01:32

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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
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ER Retrieval Pathway01:45

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In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
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Protein Folding Quality Check in the RER01:29

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ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
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Bacterial protein maturation is a tightly regulated process that ensures newly synthesized polypeptides achieve correct functional conformations. This maturation involves a series of modifications, folding events, and quality control steps, often assisted by specialized chaperone proteins.N-Terminal ModificationsThe maturation of bacterial polypeptides begins cotranslationally as the polypeptide exits the ribosome. The first amino acid, N-formylmethionine (fMet), is typically modified at the...
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Pharmacological chaperones stabilize retromer to limit APP processing.

Vincent J Mecozzi1, Diego E Berman2, Sabrina Simoes3

  • 11] Department of Biochemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts, USA. [2] Department of Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Masschusetts, USA. [3].

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Pharmacological chaperones can stabilize the retromer complex, enhancing its function in neurons. This approach may offer a new therapeutic strategy for neurodegenerative diseases like Alzheimer's by improving amyloid precursor protein processing.

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Area of Science:

  • Cellular biology
  • Neuroscience
  • Drug discovery

Background:

  • Retromer is a crucial protein complex for endosomal trafficking.
  • Dysfunctional retromer and amyloid precursor protein (APP) processing are implicated in Alzheimer's disease.
  • Targeting retromer stability offers a potential therapeutic avenue.

Purpose of the Study:

  • To investigate if pharmacological chaperones can enhance retromer stability and function.
  • To identify small molecules that stabilize the retromer complex.
  • To assess the therapeutic potential of stabilizing molecules in neuronal models of Alzheimer's disease.

Main Methods:

  • Utilized crystal structures of retromer proteins to identify weak points.
  • Performed in silico screening of small molecules for retromer stabilization.
  • Conducted in vitro thermal denaturation assays to validate molecule efficacy.
  • Treated cultured hippocampal neurons with the identified small molecule.
  • Assessed retromer protein levels, APP localization, and APP processing in neurons.

Main Results:

  • Identified a small molecule that stabilizes retromer against thermal denaturation.
  • Demonstrated that the small molecule increases retromer protein levels in neurons.
  • Showed the molecule shifts amyloid precursor protein (APP) away from the endosome.
  • Observed a decrease in pathogenic APP processing in treated neurons.

Conclusions:

  • Pharmacological chaperones can effectively enhance the stability and function of the retromer complex.
  • This strategy successfully improved APP trafficking and reduced its pathogenic processing in a neuronal model.
  • Stabilizing retromer function represents a promising therapeutic approach for neurodegenerative diseases, including Alzheimer's disease.